Process for the manufacturing of (6ar,10ar)-7-propyl-6,6a,7,8,9,10,10a,11-octahydro-[1,3]dioxolo[4',5':5,6]benzo[1,2-g]quinoline and (4ar,10ar)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol

a technology of octahydrobenzo[1,2-g]quinoline and manufacturing process, which is applied in the field of manufacturing process of (4ar, 10ar)1propyl1, 2, 3, 4, 4a, 5, 10, 10aoctahydrobenzogquinoline6, 7diol and other directions, can solve the problems of poor pharmacokinetic (pk) profile of l-dopa, and the efforts are yet to be used in clinical use for

Pending Publication Date: 2022-01-27
H LUNDBECK AS
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  • Abstract
  • Description
  • Claims
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Benefits of technology

[0022]The inventors of the present invention have developed a new process for manufacturing (4aR,10aR)-1-Propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol (compound (I)) and (6aR,10aR)-7-propyl-6,6a,7,8,9,10,10a,11-octahydro-[1,3]dioxolo[4′,5′:5,6]benzo[1,2-g]diquinoline (compound (Ib)). The invented process for the manufacture of compound (I) offers several advantages compared to the previously described process in WO2009 / 026934 including 1) a short synthetic route, 2) improved overall yield of compound (I), 3) use of resolution via diastereomeric salts instead of resolution by supercritical fluid chromatography (SFC), the latter being uneconomical and not suitable for large scale production and 4) resolution at the early stage of the synthetic route instead of late stage resolution as described in WO2009 / 026934, which reduces amount of reagents / solvents needed and amount of waste generated.

Problems solved by technology

However, after several years of treatment (i.e. the honeymoon period), complications arise due the inherent progression of the disease (i.e. sustained loss of dopaminergic neurons) as well as poor pharmacokinetic (PK) profile of L-DOPA.
However, these efforts are yet not in clinical use for the treatment of PD.
However, a known problem associated with the development of prodrugs for clinical use is the difficulties associated with predicting conversion to the parent compound in humans.
These processes include numerous steps and the use of chiral chromatography to obtain separate enantiomers and is thus not optimal for large scale production.

Method used

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  • Process for the manufacturing of (6ar,10ar)-7-propyl-6,6a,7,8,9,10,10a,11-octahydro-[1,3]dioxolo[4',5':5,6]benzo[1,2-g]quinoline and (4ar,10ar)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol
  • Process for the manufacturing of (6ar,10ar)-7-propyl-6,6a,7,8,9,10,10a,11-octahydro-[1,3]dioxolo[4',5':5,6]benzo[1,2-g]quinoline and (4ar,10ar)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol
  • Process for the manufacturing of (6ar,10ar)-7-propyl-6,6a,7,8,9,10,10a,11-octahydro-[1,3]dioxolo[4',5':5,6]benzo[1,2-g]quinoline and (4ar,10ar)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol

Examples

Experimental program
Comparison scheme
Effect test

embodiment 1

E36. The process , wherein compound (Ib) is prepared by a process comprising the following steps

step 0) according to any one of embodiments E2 to E4

step 1) according to any of embodiments E2 and E5 to E9; followed by

step 2) according to any of embodiments E13 to E16; followed by

step 3) according to any of embodiments E19 to E22.

E37. The process according to embodiment 1, wherein compound (Ib) is prepared by a process comprising the following steps

step 2) according to any of embodiments E13 to E16; followed by

step 3) according to any of embodiments E19 to E22; followed by

step 4) according to embodiment E26.

E38. The process according to embodiment 1, wherein compound (Ib) is prepared by a process comprising the following steps

step 3) according to any of embodiments E19 to E22; followed by

step 4) according to embodiment E26; followed by

step 5) according to any of embodiments E30 to E31.

E39. The process according to embodiment 1, wherein compound (Ib) is prepared by a process comprising...

example 1

on of Compounds (a2i), (a2ii) and (A2-Hemi-L-Tartrate) (Steps 0 Substep (i) Followed by Step 1 Substeps (ii) and (iii))

[0237]A mixture of 3-chloropropan-1-amine hydrochloride (24.9 g, 192 mmol), compound (A1) (20.0 g, 63.9 mmol), zinc chloride in Me-THF (1.7 ml, 3.20 mmol, 1.9 M), sodium acetate (17.3 g, 211 mmol) and sodium sulfate (4.54 g, 32.0 mmol) in Me-THF (150 mL) was stirred overnight.

[0238]Then a solution of sodium cyanoborohydride (5.22 g, 83 mmol) in Me-THF (50 mL) was added slowly at room temperature, and the mixture was stirred at 40° C. for 4 hours. The mixture was cooled to room temperature and added slowly to a stirred mixture of saturated aqueous NH4Cl solution (100 mL) and water (100 mL). The mixture was stirred for 15 minutes at room temperature. The organic phase was separated and washed with saturated aqueous NH4Cl-water mixture (100 mL, 1:1 v / v), and then with saturated aqueous NaHCO3 (2×100 mL) solution twice. The organic phase was washed with brine (100 mL), ...

example 2

on of Compound (A3) (Step 2)

[0242]A mixture of compound (A2-hemi-L-tartrate) (400 mg, 0.43 mmol), propanal (80 μL, 1.12 mol), acetic acid (49 μL, 0.86 mmol) and THF (4.0 mL) was stirred for 30 minutes. Then STAB (182 mg, 0.86 mmol) was added. The reaction mixture was stirred at room temperature for 3.5 hours. Saturated aqueous NaHCO3 solution (4 mL) was added, and the mixture was extracted with toluene. The organic extract was dried over MgSO4, filtered and evaporated to dryness to yield crude compound (A3) (167 mg, 90%) as a solid.

[0243]LC-MS: RT=2.46 minutes, [M+H]+=432.3 m / z.

[0244]1H NMR (600 MHz, CDCl3) δ 6.80 (s, 1H), 6.62 (s, 1H), 5.94 (s, 2H), 3.49-3.55 (m, 2H), 3.35-3.39 (m, 1H), 2.90 (dd, J=3.5, 13.5 Hz, 1H), 2.61-2.63 (m, 2H), 2.52 (dd, J=9.0, 13.5 Hz, 1H), 2.36-2.45 (m, 3H), 2.16 (dd, J=5.5, 14.5 Hz, 1H), 1.86-1.92 (m, 1H), 1.76-1.83 (m, 1H), 1.39-1.49 (m, 2H), 1.41 (s, 9H), 0.86 (t, J=7.5 Hz, 3H).

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Abstract

The present invention relates to a new process for manufacturing (6aR,10aR)-7-propyl-6,6 a,7,8,9,10,10a,11-octahydro-[1,3]dioxolo[4′,5′:5,6]benzo[1,2-g]quinoline with formula (Ib) below, (4aR,10aR)-1-Propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol with formula (I) below and salts thereof.Both compounds are for use in the treatment of neurodegenerative diseases and disorders such as Parkinson's Disease. The invention also relates to new intermediate compounds of said process.

Description

FIELD OF THE INVENTION[0001]The present invention relates to a process for manufacturing (4aR,10aR)-1-Propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol and (6aR,10aR)-7-propyl-6,6a,7,8,9,10,10a,11-octahydro-[1,3]dioxolo[4′,5′:5,6]benzo[1,2-g]quinoline and salts thereof which are compounds for use in the treatment of neurodegenerative diseases and disorders such as Parkinson's Disease. The invention also relates to new intermediates of said process.BACKGROUND OF THE INVENTION[0002]Parkinson's disease (PD) is a common neurodegenerative disorder that becomes increasingly prevalent with age and affects an estimated seven to ten million people worldwide. Parkinson's disease is a multi-faceted disease characterized by both motor and non-motor symptoms. Motor symptoms include resting tremor (shaking), bradykinesia / akinesia (slowness and poverty of movements), muscular rigidity, postural instability and gait dysfunction; whereas non-motor symptoms include neuropsychiatric diso...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D215/06C07D317/60
CPCC07D215/06C07D317/60C07D221/08C07D491/056C07D317/62C07D405/06
Inventor JACOBSEN, MIKKEL FOGJUHL, MARTINTHERKELSEN, FRANS DENNISSØNDERGAARD, KÅREFRIHED, TOBIAS GYLLING
Owner H LUNDBECK AS
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